CEST imaging has developed into a powerful technology with widespread interest in the MRI community. CEST imaging utilizes radiofrequency (RF) irradiation to selectively saturate solute protons. The saturation is transferred to water through rapid exchange of these protons, resulting in a reduction in water signal intensity. If the exchange rate is sufficiently fast (residence time in millisecond range) and the irradiation period sufficiently long (seconds range), the low concentration saturated solute protons are mostly replaced by high concentration unsaturated water protons so that the saturation transfer process repeats many times during the course of the RF irradiation. Consequently, the selective irradiation of these solute protons can have a discernable effect on the water signal intensity, which allows the indirect imaging of low concentration solutes through water. Furthermore, the dependence of the CEST effect on the RF irradiation duration (tsat) and strength (B1) provides additional information on the kinetics of exchange, pH, the concentration of the exchangeable protons, and the relaxation properties of water. This possibility to enhance sensitivity has led to a large variety of techniques developed for imaging low concentration diamagnetic compounds, such as Glycosoaminoglycans, Glucose/Glycogen, Glutamate, amino acids, peptides and proteins, as well as paramagnetic lanthanide complexes (PARACEST) and particles.
Among all the CEST techniques, the amide proton transfer (APT) approach, which targets the exchangeable amide protons in peptides and proteins, has become of particular interest because of several unique properties that make it favorable for in vivo application in the clinic. These include (i) the high total concentration of amide protons of endogenous mobile proteins and peptides, corresponding to about 70 mM amide proton concentration found in the mammalian brain; (ii) sufficiently low interference from the water signal due to a relatively large chemical shift between amide and water protons (˜3.6 ppm); (iii) the relatively slow exchange rate (˜30 Hz) of these amide protons that allows use of low power RF saturation pulses for their detection. To date, APT has been successfully applied to detect tumors in the brain, prostate, and breast in vivo in patients, and pH changes during ischemia in vivo in preclinical models.
In APT imaging, loss of signal can result from a number of competing mechanisms such as direct water saturation (DS), and conventional magnetization transfer contrast (MTC) from semi-solid macromolecules to water. CEST/APT experiments therefore generally require acquisition of a series of images as a function of irradiation frequency (Z-spectrum). This is followed by asymmetry analysis of the Z spectrum with respect to the water proton frequency, in which the magnetization transfer ratio (MTR) obtained at the negative offset with respect to water is subtracted from the MTR at the corresponding positive offset. While the goal of this approach originally was to remove the effects of DS and MTC, many investigators now realize that complete removal of MTC may not be possible in vivo, because MTC contrast is not completely symmetric about the water signal. In addition to MTC, it has been shown recently that contrast in Z-spectra also arises through indirect transfer of saturation induced nuclear Overhauser enhancements (NOEs) in mobile macromolecules between aliphatic/olefinic or aromatic protons and exchangeable protons, which then transfer to water (relayed transfers). Most of this signal is upfield from water (lower frequency), where the aliphatic and olefinic protons resonate. This relayed CEST contrast is a two-stage process. First, nonexchangeable protons transfer their saturation-induced Nuclear Overhauser Enhancement (NOE) via through-space dipolar coupling, and then the saturated magnetization is transferred to the water pool, most likely by chemical exchange as known from studies of the inverse exchange-relayed process in protein solution and in vivo. Notice that, contrary to the semisolid MTC effect, direct dipolar exchange through space is unlikely to occur in mobile proteins as that process is known to be much slower than exchange. This type of contrast will be referred to as “relayed-NOE CEST” (rNOE-CEST) to distinguish it from direct exchange contrast. This rNOE-CEST shares many properties with the APT contrast, but in principle has much stronger signal due to the large amount of aliphatic protons compared to amide protons. Therefore it has great potential for in vivo application.
The acquisition of detailed Z-spectra is time consuming. In addition, extra scans are often performed (e.g., water saturation shift referencing, WASSR) to allow for a voxel-based correction of the water proton frequency used as reference in the asymmetry analysis. The need to acquire Z-spectra and WASSR-spectra poses a significant practical limitation for clinical translation of APT studies, because more signal averaging could take place (to enhance sensitivity) or the experiment time could be reduced if less frequencies were needed. Recently, faster methods have been suggested, including SAFARI, employing a frequency-alternating scheme requiring four acquisitions and CERT, using two rotations, requiring only two acquisitions.
It would therefore be advantageous to provide a system and method for obtaining APT and rNOE-CEST images that provides the same results in a shorter amount of time.